Esters of 1,4-dihydropyridines and medicaments containing the same

ABSTRACT

The preparation of esters of 1,4-dihydropyridine, useful in the prevention and treatment of cardiovascular disorders such as atheroma, of the formula ##STR1## wherein X is a phenyl moiety and Y is piperazine, piperidine or an amide of a benzenecarboxylic acid, is described.

This is a division of application Ser. No. 637,216, filed July 20, 1984,now U.S. Pat. No. 4,656,181.

The present invention relates to new 1,4-dihydropyridines, to processesfor their preparation and to medicaments containing the same, suchmedicaments being preferably used for their action on the blood vessels,and in particular as agents against coronary diseases or asanti-atheromatic agents. The applicant has discovered the importantinfluence that have on the coronary vessels the new esters of1,4-dihydropyridines (I) and their salts of the general formula:##STR2## in which: R stands for a hydrogen atom, for a saturated or anunsaturated hydrocarbon radical or an alkylmorpholinic group,

R₂ and R₃, which can be identical or different stand for a hydrogenatom, an alkyl group or an alkoxyalkyl group,

R₄ stands for a hydrogen atom or a straight alkyl chain,

n is a number equaling 0, 1, 2 or 3,

X stands for an aryl radical which can have one to three substituentsnitro, cyano, azido, alkyl, alkoxy, hydroxy, acyloxy, carbaloxy, amino,acylamino, alkylamino, S(O)_(m) -alkyl where m equals 0, 1 or 2, phenyl,trifluoromethyl or halo, with these substituents being identical ordifferent, a benzyl, styryl, cycloalkyl, cycxloalkenyl group, or anaphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, diphenyl, furyl,pyrryl or thiophenyl radical which can be substituted by an alkyl,alkoxy, dialkylamino, nitro or halo group,

R₁ is a hydrocarbon radical which can be straight or branched,saturated, unsaturated or cyclic; it can also be interrupted by one ortwo atoms of oxygen or sulfur and can be substituted by one or twohydroxyl groups; R₁ can also designate the ##STR3## group; the twosubstituents Y can be identical or different and have the followingstructures:

Y designates N-substituted amides of nicotinic, salicylic and4-hydroxybenzoic acids or N-substituted piperazines of the followingformula ##STR4## where R₅ is an alkyl, acyl, or an arylsulfonyl radical.Y can also designate another group of products having for formula--OOC--R₆ and --O--R₆, where R₆ is a hydrocarbon radical which can besaturated or cyclic, branched or not, heterocyclic or aromatic, andwhich can be substituted with one or two nitro, halo, hydroxy, acetyl,alkoxy, trifluoromethyl or acylamino groups. Y can also designate a2-tetrahydrofuryl or a N-(4-benzoyl-piperidinyl) group.

These products (I) can be prepared by using the following processes:

(a) By reacting esters of β-ketocarboxylic acids of the formula (II)

    R.sub.2 --CO--CH.sub.2 --COOR.sub.1                        (II)

(where R₁ and R₂ are defined as above) with amines of the formula (III)

    R--NH.sub.2                                                (III)

for obtaining enamines of the following formula (IV) ##STR5## (where R,R₁ and R₂ are defined as above) which are eventually isolated andthereafter reacted with an ylidenic derivative of the formula (V)##STR6## (where X, R₃, R₄, n an Y are defined as above) which areobtained by reacting aldehydes of the formula (VI)

    X--CHO                                                     (VI)

(where X is defined as above) with esters of β-ketocarboxylic acids ofthe formula (VII): ##STR7## (where R₃, R₄, n and Y are defined asabove); or

(b) By reacting β-ketocarboxylic acids of the formula (VII) with aminesof the formula (III) for obtaining enamines of the formula ##STR8##(where R, R₃, R₄, n and Y are defined as above) which are eventuallyisolated and thereafter reacted with ylidenic derivatives of the formula(IX) ##STR9## (where X, R₁ and R₂ are defined as above) which areobtained by reacting aldehydes of the formula (VI) with esters ofβ-ketocarboxylic acids of the formula (II); or

(c) By reacting esters of β-ketocarboxylic acids of the formula (II)with enamines of the formula (VIII) and aldehydes of the formula (VI);or

(d) By reacting esters of β-ketocarboxylic acids of the formula (VII)with enamines of the formula (IV) and aldehydes of the formula (VI); or

(e) By reacting two moles of β-ketocarboxylic acids of the formula (VII)with one mole of amine of the formula (III) and one mole of aldehyde ofthe formula (VI); or

(f) In certain cases, where Y designates a group with a substituted atomof oxygen or nitrogen, the compound (I) can also be obtained by reactingthe 1,4-dihydropyridine of the formula (X) ##STR10## (where X, R, R₁, R₂R₃, R₄ and n are defined as above and Hal stands for a halogen atom)with a compound of the formula (XI)

    HY                                                         (XI)

(where Y is defined as above and H is capable of a substitutionreaction). When desired, salts of the products prepared according to theprocesses (a) to (f) can be prepared by using an acid. In formula (I),the saturated or unsaturated hydrocarbon radical R is preferably astraight or a branched C₁ to C₄ alkyl such as methyl, ethyl, n-propyl,isopropyl, n-butyl and tert-butyl, or a straight or a branched C₂ to C₄alkenyl such as ethenyl, 1-propenyl, 2-propenyl and butenyl. R can alsobe an alkylmorpholinic radical such as ethylmorpholinyl andpropylmorpholinyl.

In the formula (I), the saturated or unsaturated hydrocarbon R₁ ispreferably a straight or a branched C₁ to C₄ alkyl, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl or astraight or a branched C₂ to C₄ alkenyl such as ethenyl, 1- or2-propenyl, and butenyl. R₁ can also be a cycloalkyl with preferably 5or 6 atoms of carbon, such as cyclopentyl, cyclohexyl, and3,3,5-trimethylcyclohexyl. When an oxygen or a sulfur is included in thehydrocarbon chain, R₁ can be represented by the radicals --W--O--Z and--W--S--Z, where W designates a straight or a branched C₁ to C₃alkylene, such as methylene, ethylene and isopropylene, an Z designatesa straight or a branched C₁ to C₄ alkyl radical such as methyl, ethyl,n-propyl, isopropyl, n-butyl and tert-butyl. R₁ can also be the cyclic2-tetrahydrofurfurylic radical.

In the formula (I), the R₂ and R₃ alkyl groups are preferably straightor branched C₁ to C₄ alkyls, such as methyl, ethyl, n-propyl, isopropyl,and tert-butyl. The R₂ and R₃ alkoxyalkyl groups are preferably--W--O--Z radicals with W an Z defined as above.

In the formula (I), the R₄ alkyl group is preferably a straight C₁ to C₂alkyl (methyl or ethyl).

In the formula (I), the aryl group X (which can be substituted) is anaryl with preferably 6 to 10 carbons, and in particular 6 carbons in thearyl portion. Phenyl or naphthyl groups (with possible substituents) canbe given as examples of such aryl groups. The aryl X can have one orseveral--preferably 1 to 3 and in particular 1 or 2--substituents, whichcan be identical or different. These substituents can for example bephenyl or alkyl groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and tert-butyl; they can also be alkoxy groups such asmethoxy, ethoxy, propyloxy and isopropyloxy; trifluoromethyl; hydroxy;halo, preferably fluoro, chloro, bromo and iodo; cyano, nitro, azido,amino, monoalkyl or dialkylamino with preferably 1 to 4 and inparticular 1 or 2 carbons in the alkyl group such as for examplemethylamino, methylethylamino, isopropylamino and diethylamino;carbalkoxy such as carbmethoxy and carbethoxy; acylamino group such asacetylamino and propionylamino; acyloxy group such as acetyloxy andpropionyloxy; S(O)_(m) -alkyl group where m equals 0, 1 or 2 and thealkyl group has preferably 1 to 4 carbons and in particular 1 to 2carbons, such as methylthio, ethylthio, methylsulfoxyl, ethylsulfoxyl,methylsulfonyl and ethylsulfonyl. The alkyl and alkoxy groups present assubstituents on the naphtyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl,diphenyl, furyl or pyrryl group X are alkyl or alkoxy radicals with astraight or a branched chain such as methyl, ethyl, n-propyl, isopropyl,n-butyl, tert-butyl, as well as methoxy, ethoxy, n-propoxy, isopropoxy,and tert-butoxy. The halogen present as a substituent on the X groupsgiven above is fluorine, chlorine, bromine or iodine. The dialkylaminogroup also present as substituent on the X groups contains preferably 1to 4 and in particular 1 or 2 carbons in the alkyl groups. The followingexamples of alkyl groups can be given: methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl and tert-butyl.

In the formula (I), the group Y stands preferably for N-substitutedamides of nicotinic, salicylic and 4-hydroxybenzoic acids and formonoalkylated, monoacylated and sulfonylated piperazines of thefollowing formula ##STR11## where R₅ is a straight or branched,saturated or unsaturated alkyl such as methyl, ethyl, isopropyl, benzyl,vinyl and cinnamyl. R₅ also stands for acyl radicals, such as acetyl,2-furoyl, 2-thiophenecarbonyl and cinnamoyl. R₅ further stands forarylsulfonyl radicals such as benzenesulfonyl; these aromatic radicalscan in turn be substituted by one or several alkyl groups such asmethyl, ethyl and trifluoromethyl, alkoxy such as methoxy or ethoxy,acetylamine, one or several halogens such as chlorine, fluorine bromineand iodine. Y further stands for --OOC--R₆ and --O--R₆ groups, where R₆stands for a saturated or an unsaturated hydrocarbon, preferably for astraight or a branched alkyl with 1 to 4 carbons, and in particular with1 to 3 carbons such as methyl, ethyl and isopropyl; a cyclic hydrocarbongroup such as cyclohexyl; an alkenyl group such as ethenyl or2-propenyl; a heterocyclic group such as furyl, thiophenyl and pyridyl;an aromatic group such as phenyl. The following examples of substituentswhich can be present on this phenyl group can be given: nitro, halo (forexample chloro and bromo), alkoxy (methoxy, ethoxy), hydroxy, acetyl,trifluoromethyl and acylamino (acetylamino).

The salts of the compounds of formula (I) are all salts resulting fromthe addition of acids which are nontoxic and physiologically acceptable.The following examples of inorganic and organic acids which form saltswith the compounds of formula (I) can be given: halohydric acids such ashydrochloric acid and hydrobromic acid, phosphonic acids, sulfuric acid,nitric acid, monocarboxylic acids, dicarboxylic acids, hydroxycarboxylicacids such as citric acid, malic acid, succinic acid, fumaric acid,tartaric acid, citric acid, salicylic acid, lactic acid,1,5-naphthalenecarboxylic acid, methanesulfonic acid and toluenesulfonicacid.

The conditions in which the reactions (a) to (f) are performed are thefollowing:

Is considered as a diluent water and all the inert organic solvents.These are preferably alcohols such as methanol, ethanol, isopropanol andn-butanol; ethers, for example lower dialkyl ethers such as diethylether or cyclic ethers such as tetrahydrofuran and dioxane; loweraliphatic carboxylic acids such as acetic acid and propionic acid; lowerdialkyl formamides such as dimethylformamide; lower alkylnitriles suchas acetonitrile; dimethylsulfoxyde, liquid heteroaromatic bases such aspyridine; mixtures of such diluents, including water. The reaction canalso be carried out without using a diluent.

The reaction temperatures can vary from approximately 20° C. to 150° C.,and preferably between 50° C. and 100° C. The reaction can in particularbe carried out at the boiling temperature of the diluent. The reactioncan be carried out at atmospheric pressure, but higher pressures canalso be used. The reactants are preferably used in approximately a molarratio. Ammonia in preferably used in excess, e.g. of one to two moles.The molar ratio can vary within large limits without affecting theresults.

The reaction time varies between 45 minutes and 10 hours.

The product obtained according to the process of the invention isseparated and isolated according to known practices, such asrecrystallisation in an appropriate solvent or a mixture of appropriatesolvents.

The characterization of the structures of the different compounds (I)was carried out using quantitative elemental analysis and IR and NMRanalyses.

Further to the products described in the Examples, the new activesubstances include the following:

2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-pyridyl)1,4-dihydropyridine-3-carboxylate,

2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylate,

2-(4-acetylaminophenoxy)ethyl4-(2,3-dichlorophenyl)-2,6-diethyl-5-(-tetrahydrofurfuryloxycarbonyl)-1,4-dihydropyridine-3-carboxylate,

bis-2-(N-nicotinoylamino)ethyl2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate,

2-(N-nicotinoylamino)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-pyridyl)-1,4-dihydropyridine-3-carboxylate,

2-(N-nicotinoylamino)ethyl2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-4-(3-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylate,

2-(N-nicotinoylamino)ethyl4-(2,3-dichlorophenyl)-2,6-dimethyl-5-(2-methylthioethoxycarbonyl-1,4-dihydropyridine-3-carboxylate,

2-(N-salicylamido)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-pyridyl)-1,4-dihydropyridine-3-carboxylate,

2-(N-salicylamido)ethyl4-(2,3-dichlorophenyl)-2,6-dimethyl-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylate,

2-(4-(2-furoyl)-1-piperazinyl))ethyl2,6-dimethyl-5-methoxycarbonyl-4-(2-pyridyl)-1,4-dihydropyridine-3-carboxylate,

2-(4-(2-furoyl)-1-piperazinyl)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylate,

2-(4-(2-furoyl)-1-piperazinyl)ethyl4-(2,3-dichlorophenyl)-2,6-dimethyl-5-isopropoxycarbonyl-1,4-dihydropyridine-3-carboxylate,

2-(N-salicylamide)ethyl4-(2,3-dichlorophenyl)-2,6-dimethyl-1-(2-(N-morpholine)ethyl)-5-(2-methoxyethoxycarbonyl)-3-carboxylate,

2-(4-cinnamoyl-1-piperazinyl)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylate,

2-(4-(4-methoxy)cinnamoyl-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-pyridyl)-1,4-dihydropyridine-3-carboxylate,

2-(4-cinnamoyl-1-piperazinyl)ethyl4-(2,3-dichlorophenyl)-2,6-dimethyl-5-(2-methylthioethoxycarbonyl)-1,4-dihydropyridine-3-carboxylate.

As was indicated previously, the applicant has found that the compoundsof the invention can be advantageously used as pharmacologically activesubstances in medicaments used for the treatment of various diseases. Asexamples of such diseases, one can mention diseases of the coronaryvessels, for which these compounds are particularly effective. Theapplicant has found that the compounds of the invention generally haveanti-atheromatic properties, and can therefore exert a protective effectagainst necrosis.

In experiments carried out on animals, it was found that whenadministered at the same therapeutical level, the new compounds weremore active and less toxic than similar known therateutical agents.

To achieve the desired therapeutical effects, the new products can beadministered orally under an appropriate form. The doses which are thenused can vary between 5 and 500 mg of active ingredient which can becombined, when desired, with an inert excipient or an additional activeingredient.

These doses can be used in preventive or curative treatments.

EXAMPLE 1 ##STR12##

15 g (0.04 moles) of 2-(4-acetylaminophenoxy)-ethyl2-(3-nitrobenzilidene)acetylacetate and 4.19 g (0.04 moles) of methyl3-aminocrotonate are heated for 4 hours under reflux in 40 ml ofethanol. The solution is cooled to 7° C. to obtain2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in isopropanol--at202°-204° C. The yield was 68% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.26 H.sub.27 N.sub.3 O.sub.8 :                                        % C        % H    % N                                               ______________________________________                                        Calculated  61.29        5.35   8.25                                          Found       60.93        5.52   8.23                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 3210, 3080, 1700, 1670, 1510, 1350,1240, 1210, 1090, 840, 780, 700.

NMR spectrum (δ, CDCl₃ +DMSO-d₆): p.p.m: 9.4(1H, s); 8.6 (1H, s); 8-6.6(8H, m); 5(1H, s); 4.4-4 (4H, m); 3.6 (3H, s) 2.3 (6H, s); 2(3H, s).

EXAMPLE 2 ##STR13##

8.3 g (0.02 moles) of 2-(4-acetylaminophenoxy)ethyl2-(3-nitrobenzylidene)acetylacetate and 3.2 g (0.02 moles) of2-methoxyethyl 3-aminocrotonate are heated for 8 hours under reflux in25 ml of ethanol. The solution is cooled to -5° C. to obtain2-(4-acetylaminophenyl)ethyl2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-4-(3-nitrophenyl-1,4-dihydropyridine-3-carboxylateas a yellow powder melting--after recrystallisation in ethanol--at95°-98° C. The yield is 64% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.26 H.sub.31 N.sub.3 O.sub.9 :                                        % C        % H    % N                                               ______________________________________                                        Calculated  60.75        5.64   7.59                                          Found       60.55        5.79   7.42                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3170, 1710, 1700, 1540, 1520, 1360, 1220,1120, 1100, 870, 710.

NMR spectrum (δ, CDCl₃): p.p.m: 8.2-6.6 (10H, m); 5.2 (1H, s); 4.4-4(6H, m); 3.6-3.4 (2H, m); 3.3 (3H, s); 2.3 (6H, s); 2.1 (3H, s).

EXAMPLE 3 ##STR14##

15 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl2-(3-nitrobenzylidene)acetylacetate and 6.37 g (0.04 moles) of2-methylthioethyl 3-aminocrotonate are heated under reflux in 30 ml ofethanol during 8 hours. The solution is then cooled to -5° C. to obtain2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-(2-methylthioethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol--at 76°C.-80° C. The yield is 80% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.28 H.sub.31 N.sub.3 O.sub.8 S:                                        % C  % H        % N    % S                                         ______________________________________                                        Calculated   59.04  5.49       7.38 5.63                                      Found        59.92  5.41       7.55 5.81                                      ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3320, 3100, 1700, 1670, 1530, 1510, 1350,1210, 1120, 1010, 820, 700.

NMR spectrum (δ, CDCl₃): p.p.m: 8.1-6.6 (10H, m); 5.1 (1H, s); 4.4-4(6H, m); 2.6 (2H, t); 2.3 (6H, s); 2.2 (3H, s); 2.1 (3H, s).

EXAMPLE 4 ##STR15##

15 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl2-(2-nitrobenzylidene)acetylacetate and 4.19 g (0.04 moles) of methyl3-aminocrotonate are heated under reflux in 35 ml of ethanol for 10hours. The solution is then cooled at -5° C. to obtain2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxyas yellow crystals melting--after recrystallisation in ethanol--at163°-166° C. The yield is 56% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.26 H.sub.27 N.sub.3 O.sub.8                                          % C        % H    % N                                               ______________________________________                                        Calculated  61.29        5.35   8.25                                          Found       61.27        5.36   7.94                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3300, 3200, 1680, 1540, 1520, 1220, 1130,1030, 840, 720.

NMR spectrum (δ, CDCl₃ +DMSO-d₆): p.p.m: 9.2 (1H, s); 8.2 (1H, s);7.6-6.6 (8H, m); 5.7 (1H, s); 4.2 (4H, m); 3.5 (3H, s); 2.3 (6H, d); 2.1(3H, s).

EXAMPLE 5 ##STR16##

10 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl 3-aminocrotonate,10.04 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl acetylacetate and5.43 g (0.04 moles of 3-nitrobenzaldehyde are heated under reflux in 35ml of ethanol for 1.5 hours. The solution is then allowed to cool downto room temperature to obtain bis-2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylatewith one molecule of ethanol as a pale yellow powder melting--afterrecrystallisation in ethanol--at 142°-152° C. The yield is 50% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.35 H.sub.36 N.sub.4 O.sub.10.C.sub.2 H.sub.6 O                       % C        % H    % N                                               ______________________________________                                        Calculated  61.83        5.89   7.79                                          Found       62.08        5.79   8.02                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3330, 1690, 1670, 1540, 1520, 1350, 1250,1120, 720.

NMR spectrum (δ, DMSO-d₆): p.p.m: 9.7 (2H, s); 9 (1H, s); 8-6.6 (12H,m); 5 (1H, s); 4.4-4 (8H, m); 3.4 (2H, q); 2.3 (6H, s); 2 (6H, s); 1.1(3H, t).

EXAMPLE 6 ##STR17##

12.28 g (0.03 moles) of 2-(4-acetylaminophenoxy)ethyl2-(3-nitrobenzylidene)acetylacetate and 3.85 (0.03 moles) of ethyl3-aminocrotonate are heated under reflux in 30 ml of ethanol for 8hours. The solution is then cooled to -5° C. to obtain2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol--at198°-200° C. The yield is 75% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.27 H.sub.29 N.sub.3 O.sub.8 :                                        % C        % H    % N                                               ______________________________________                                        Calculated  61.94        5.58   8.03                                          Found       61.88        5.87   7.55                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 3280, 3220, 3080, 1695, 1665, 1530,1510, 1310, 1240, 1200, 1090, 930, 840, 780, 700.

NMR spectrum (δ, CDCl₃): p.p.m: 9.7 (1H, s); 9 (1H, s); 8-6.6 (8H, m); 5(1H, s); 4.2 (6H, m); 2.4 (6H, s); 2.1 (3H, s); 1.1 (3H, t).

EXAMPLE 7 ##STR18##

15 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl2-(3-nitrobenzylidene)acetylacetate and 6.88 g (0.04 moles) of2-ethylthioethyl 3-aminocrotonate were heated under reflux in 35 ml ofethanol for 8 hours. The solution was then cooled to -5° C. to obtain2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-(2-ethylthioethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas a yellow powder melting--after recrystallisation in ethanol--at100°-104° C. The yield is 60% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.29 H.sub.33 N.sub.3 O.sub.8 S:                                        % C  % H        % N    % S                                         ______________________________________                                        Calculated   59.68  5.70       7.20 5.49                                      Found        59.19  6.02       7.19 5.90                                      ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3440, 3340, 3150, 1730, 1700, 1560, 1380,1250, 1150, 860, 740.

NMR spectrum (δ, SDCl₃): p.p.m.: 8-6.6 (10H, m); 5.1 (1H, s); 4.4-4 (6H,m); 2.6 (4H, m); 2.3 (6H, s); 2.1 (3H, s); 1.2 (3H, t).

EXAMPLE 8 ##STR19##

15 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl2-(2-nitrobenzylidene)acetylacetate and 5.79 g (0.04 moles) of2-methoxyethyl 3-aminocrotonate are heated under reflux in 35 ml ofethanol for 10 hours. The solution is then allowed to cool down to roomtemperature to obtain 2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting with decomposition--after recrystallisationin ethanol--at 94°-105° C. The yield is 84% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.28 H.sub.31 N.sub.3 O.sub.9                                          % C        % H    % N                                               ______________________________________                                        Calculated  60.75        5.64   7.59                                          Found       60.48        5.64   7.59                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3300, 1710, 1655, 1540, 1520, 1250, 1200,890, 830, 720.

NMR spectrum (δ, DMSO-d₆): p.p.m: 9.8 (1H, s); 9 (1H, s); 7.6-6.6 (8H,m); 5.6 (1H, s); 4.1 (6H, m); 3.4 (2H, m); 3.1 (3H, s); 2.2 (5H,s); 2(3H, s).

EXAMPLE 9 ##STR20##

15 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl2-(2-nitrobenzylidene)acetylacetate and 5.21 g (0.04 moles) of isopropyl3-aminocrotonate are heated under reflux in 35 ml of ethanol for 10hours. The solution is then cooled to -5° C. to obtain2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-isopropoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylatewith half a molecule of ethanol as yellow crystals melting--afterrecrystallisation in ethanol--at 103°-112° C. The yield is 35% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.28 H.sub.31 N.sub.3 O.sub.8.1/2C.sub.2 H.sub.6 O                     % C        % H    % N                                               ______________________________________                                        Calculated  62.13        6.11   7.50                                          Found       62.05        5.98   7.82                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3350, 1705, 1540, 1520, 1210, 1110, 835,720.

NMR spectrum (δ, CDCl₃): p.p.m: 7.9-6.4 (10H, m); 5.8 (1H, s); 4.9 (1H,h); 4.3 (2H, sl); 4.1 (2H, sl); 3.7 (1/2 2H, q); 2.3 (6H, d); 2.1 (3H,s); 1.3-0.9 (6H+3H, d+t).

EXAMPLE 10 ##STR21##

12 g (0l03 moles) of 2-(4-acetylaminophenoxy)ethyl2-(3-nitrobenylidene)acetylacetate and 5.92 g (0.03 moles) of2-isopropylthioethyl 3-aminocrotonate are heated under reflux in 30 mlof ethanol for 8 hours. The solution is then cooled to -5° C. to obtain2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-(2-isopropylthioethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in aqueusethanol--at 142°-144° C. The yield was 42% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.30 H.sub.35 N.sub.3 S                                                 % C  % H        % N    % S                                         ______________________________________                                        Calculated   60.29  5.90       7.03 5.36                                      Found        60.35  6.10       6.97 5.65                                      ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3300, 3260, 3100, 1670, 1620, 1530, 1510,1350, 1210, 1120, 1020, 920, 820, 750, 700.

NMR spectrum (δ, CDCl₃ +DMSO-d₆): p.p.m.: 9.2 (1H, s); 8.3 (1H, s);8-6.6 (8H, m); 5.1 (1H, s); 4.4-4 (6H, m); 3-2.5 (3H, m); 2.35 (6H, s);2.1 (3H, s); 1.2 (6H, d).

EXAMPLE 11 ##STR22##

10 g (0.04 moles) of methyl 2-(3-methoxybenzylidene)acetylacetate and11.88 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl 3-aminocrotonateare heated under reflux in 50 ml of ethanol for 8 hours. The solution isthen cooled to -5° C. to obtain 2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-methoxyphenyl)-1,4-dihydropyridine-3-carboxylatewith half a molecule of ethanol as white needles melting--afterrecrystallisation in ethanol--at 88°-92° C. The yield is 50% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.27 H.sub.30 N.sub.2 O.sub.7.1/2C.sub.2 H.sub.6 O                     % C        % H    % N                                               ______________________________________                                        Calculated  64.98        6.43   5.41                                          Found       64.80        6.68   5.44                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3400, 1710, 1670, 1670, 1520, 1500, 1220,1120, 1055, 830, 780, 720.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 9.7 (1H, s); 8.8 (1H, s); 7.6-6.6(8H, m); 4.9 (1H, s); 4.2 (4H, m); 3.65 (3H, s); 3.55 (3H, s); 2.3 (6H,s); 2 (3H, s); 1.1 (1/2 3H,t).

EXAMPLE 12 ##STR23##

15 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl2-(3-nitrilobenzylidene)acetylacetate and 5.21 g (0.04 moles) ofisopropyl 3-aminocrotonate are heated under reflux in 35 ml of ethanolfor 8 hours. 15 ml of the solvent are then evaporated, and the remainingfraction is cooled to -5° C. to obtain 2-(4-acetylaminophenyl)ethyl2,6-dimethyl-5-isopropoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas a pale yellow powder melting--after recrystallisation in ethanol--at146°-148° C. The yield is 50% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.28 H.sub.31 N.sub.3 O.sub.8                                          % C        % H    % N                                               ______________________________________                                        Calculated  62.56        5.81   7.82                                          Found       62.89        5.99   8.03                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3400, 3300, 3080, 1700, 1675, 1530, 1510,1350, 1240, 1210, 1100, 1070, 840, 790, 700.

NMR spectrum (δ, CDCl₃): p.p.m.: 8-6.5 (10H, m); 5 (1H+1H, s+m); 4.3(2H, m); 4.05 (2H, m); 2.3 (6H, s); 2.1 (3H, s); 1.1 (6H, q).

EXAMPLE 13 ##STR24##

25 g (0.07 moles) of 2-(N-nicotinoylamino)ethyl2-(3-nitrobenzylidene)acetylacetate and 7.51 g (0.07 moles) of methyl3-aminocrotonate are heated uner reflux in 70 ml of ethanol for 45minute. The solution is the cooled to room temperature to obtain2-(N-nicotinoylamino)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol--at207°-209° C. The yield is 70% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.24 H.sub.24 N.sub.4 O.sub.7                                          % C        % H    % N                                               ______________________________________                                        Calculated  60.00        5.03   11.66                                         Found       59.99        5.20   11.20                                         ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3340, 3220, 3080, 2960, 1700, 1670, 1510,1350, 1210, 1120, 1040, 780, 750, 700.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 9.2-7.3 (10H,m); 5.1 (1H, s); 4.2(2H, m); 3.6 (5H, s); 2.4 (6H, s).

EXAMPLE 14 ##STR25##

10 g (0.03 moles) of 2-(N-nicotinoylamino)ethyl2-(3-nitrobenzylidene)acetylacetate and 3.37 g (0.03 moles) of ethyl3-aminocrotonate are heated uner reflux in 35 ml of ethanol for 8 hours.15 ml of the solvent are then evaporated and the remaining fraction iscooled to -5° C. to obtain 2-(N-nicotinoylamino)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation inethanol--153°-155° C. The yield is 32% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.25 H.sub.26 N.sub.4 O.sub.7                                          % C        % H    % N                                               ______________________________________                                        Calculated  60.72        5.30   11.33                                                     61.02        5.46   11.53                                         ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3300, 3220, 3080, 1690, 1640, 1530, 1490,1145, 1200, 1090, 780, 740, 700.

NMR spectrum (δ, SDCl₃ +DMSO-d₆): p.p.m.: 9-7.2 (10H, m); 5.1 (1H, s);4.3-3.4 (6H, m); 2.35 (6H, s); 1.2 (3H, t).

EXAMPLE 15 ##STR26##

10.79 g (0.03 moles) of 2-(N-nicotinyolamino)ethyl2-(3-nitrobenzylidene)acetylacetate and 4.93 g (0.03 moles) of2-methylthioethyl 3-aminocrotonate are heated under reflux in 30 ml ofethanol for 10 hours. The solvent is then evaporated and an orange oilis obtained which is transformed into the corresponding chlorhydrate byfirst dissolving the oil in 100 ml of absolute ethanol and then byadding 100 ml of ethyl ether saturated with hydrogen chloride. Byevaporating the solvent the chlorhydrate of 2-(N-nicotinoylamino)ethyl2,6-dimethyl-5-(2-methylthioethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateis obtained which after recrystallisation from ethanol-ether formsyellow crystals melting and decomposing at the same time at 120°-130° C.The yield is 25% of the theoretical yield

    ______________________________________                                        Analysis for C.sub.26 H.sub.28 N.sub.4 O.sub.7 S.HCl                                  % C    % H    % N      % S  % Cl                                      ______________________________________                                        Calculated                                                                              54.12    5.07   9.71   5.56 6.14                                    Found     54.33    5.18   9.89   4.65 6.24                                    ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3380, 3250, 3080, 1685, 1539, 1490, 1350,1220, 1120, 1020, 830, 740, 710, 680.

NMR spectrum (δ, CDCl₃ +DMSO-d₆): p.p.m.: 13.6 (1H, sl); 9.4-7.2 (10,m); 5.05 (1H, s); 4,2 (4H, m); 3.6 (2H, m); 2.6 (2H, t); 2.4 (6H, s);2.1 (3H, s).

EXAMPLE 16 ##STR27##

14.15 g (0.06 moles) of methyl 2-(3-nitrobenzylidene)acetylacetate and15 g (0.06 moles) of 2-(N-salicylamido)ethyl 3-aminocrotonate are heatedunder reflux in 55 ml of ethanol for 6 hours. The solvent is thenevaporated, and the remaining oil dissolved in 10 ml of boilingmethanol. This solution is cooled to room temperature to obtain2-(N-salicylamido)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol--at165°-170° C. The yield is 83% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.25 H.sub.25 N.sub.3 O.sub.8                                          % C        % H    % N                                               ______________________________________                                        Calculated  60.60        5.09   8.48                                          Found       60.54        5.12   8.70                                          ______________________________________                                    

IR spectrum (KBr) ν(cm⁻¹): 3460, 3380, 1710, 1660, 1545, 1490, 1360,1210, 1130, 1095, 755, 705.

NMR spectrum (δ, CDCl₃): p.p.m.: 12.3 (1H, s); 8.6-6.7 (10H, m); 5.1(1H, s); 4.2 (2H, m); 3.55 (5H, sd); 2.35 (6H, s).

EXAMPLE 17 ##STR28##

12 g (0.05 moles) of methyl 2-(3-nitrobenzylidene)acetylacetate and 14.8g (0.05 moles) of 2-(4-(2-furoyl)-1-piperazinyl)ethyl 3-aminocrotonateare heated under reflux in 45 ml of ethanol for 8 hours. The solvent isthen evaporated and the removing oil is transformed into thecorresponding chlorhydrate by dissolution in 100 of ethyl ethersaturated with hydrogen chloride. The solvent is evaporated and theresidue triturated with boiling ethanol to obtain the chlorhydrate of2-(4-(2-furoyl)-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas a pale yellow powder melting while at the same time decomposing at237°-240° C. The yield is 40% of theoretical yield.

    ______________________________________                                        Analysis for C.sub.27 H.sub.30 N.sub.4 O.sub.8 HCl                                      % C  % H        % N    % Cl                                         ______________________________________                                        Calculated  56.40  5.43        9.74                                                                              6.17                                       Found       56.71  5.60       10.42                                                                              6.41                                       ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3240, 3120, 2600, 2530, 1710, 1670, 1540,1495, 1360, 1220, 1135, 890, 760, 710.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 9.2 (1H, sl); 8-6.5 (8H, m); 5 (1H,s); 4.4 (4H, sl); 3.7-3 (3H+8H, m); 2.3 (6H, d).

EXAMPLE 18 ##STR29##

17.32 g (0.07 moles) of ethyl 2-(3-nitrobenzylidene)acetylacetate and20.22 g (0.07 moles) of 2-(4-(2-furoyl)-1-piperazinyl)ethyl3-aminocrotonate are heated under reflux in 60 ml of ethanol for 7hours. The solution is the cooled to -5° C. to obtain2-(4-(2-furoyl)-1-piperazinyl)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol--at149°-152° C. The yield is 65% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.28 H.sub.32 N.sub.4 O.sub.8                                          % C        % H    % N                                               ______________________________________                                        Calculated  60.86        5.84   10.14                                         Found       61.14        5.97   10.08                                         ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3280, 3220, 3100, 2980, 1700, 1620, 1540,1500, 1360, 1280, 1210, 1110, 1030, 790, 750, 720.

NMR spectrum (δ,CDCl₃): p.p.m.: 8.1-6.4 (8H, m); 5.1 (1H, s); 4.2 (4H,m); 3.7 (4H, m); 2.7-2.2 (6H+6H, m+s); 1.2 (3H, t).

EXAMPLE 19 ##STR30##

11.78 g (0.04 moles) of ethyl 2-(3-nitrobenzylidene)acetylacetate and15.37 g (0.04 moles) of 2-(4-cinnamoyl-1-piperzinyl)ethyl3-aminocrotonate are heated under reflux in 45 ml of ethanol for 8hours. The solution is the cooled to -5° C. to obtain2-(4-cinnamoyl-1-piperazinyl)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol--at164°-172° C. The yield is 56% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.32 H.sub.36 N.sub.4 O.sub.7                                          % C        % H    % N                                               ______________________________________                                        Calculated  65.29        6.16   9.52                                          Found       65.49        6.20   9.78                                          ______________________________________                                    

IR spectrum (Kbr): ν(cm⁻¹): 3300, 3250, 3120, 1710, 1650, 1600, 1540,1360, 1280, 1210, 1100, 785, 760, 715.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.2-6.7(12H, m); 5.1(1H, s); 4.2(4H,m); 3.6(4H, s); 2.6-2.2(6H+6H, m+s); 1.2(3H, t).

EXAMPLE 20 ##STR31##

15 g (0.05 moles) of 2-tetrahydrofurfuryl2-(3-(nitrobenzylidene)acetylacetate and 5.41 g (0.05 moles) of methyl3-aminocrotonate are heated under reflux in 50 ml of ethanol for 8hours. The solution is then cooled down to -5° C. to obtain2-tetrahydrofurfuryl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol--at135°-140° C. The yield is 50% of the theorical yield.

    ______________________________________                                        Analysis for C.sub.21 H.sub.24 N.sub.2 O.sub.7                                          % C        % H    % N                                               ______________________________________                                        Calculated  60.57        5.81   6.73                                          Found       60.51        5.99   6.39                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3470, 3100, 2950, 2870, 1710, 1650, 1530,1480, 1345, 1220, 1120, 1020, 825, 780, 740.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.1-7.2(4H, m); 6.8(1H, s); 5.1(1H, s);4.1(3H, sd); 3.9-3.6(2H+3H, m+s); 2.35(6H, s); 1.8(4H, m).

EXAMPLE 21 ##STR32##

15 g (0.08 moles) of 2-tetrahydrofurfuryl 3-aminocrotonate, 18.33 g(0.08 moles) of 3,3,5-trimethycyclohexyl acetylacetate and 12.24 g (0.08moles) of nitrobenzaldehyde are heated under reflux in 65 ml of ethanolfor 12 hours. 35 ml of water are then added to the mixture, which iscooled to -5° C. A yellow oil is thus obtained which is separated bydecanting and dried in a desiccator. 3,3,5-trimethylcyclohexyl2,6-dimethyl-4-(3-nitrophenyl)-5-(2-tetrahydrofurfuryloxycarbonyl)-1,4-dihydropyridine-3-carboxylateis obtained as yellow crystals melting--after recrystallisation inethanol--at 159°-162° C. The yield is 304 of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.29 H.sub.38 N.sub.2 O.sub.7                                          % C        % H    % N                                               ______________________________________                                        Calculated  66.14        7.27   5.32                                          Found       66.41        7.57   5.23                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3380, 2950, 1700, 1520, 1490, 1345, 1200,1090, 790, 740, 710.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.1-7.2(4H, m); 6.5(1H, s); 5.2(1H, d);5(1H, s); 4.1-3.8(s+t, 3H+2H); 2.3(6H, d); 2-0.6(m, 2OH).

EXAMPLE 22 ##STR33##

15 g (0.08 moles) of 2-tetrahydrofurfuryl 3-aminocrotonate, 11.51 g(0.08 moles) of ally acetylacetate and 12.24 g (0.08 moles) of3-nitrobenzaldehyde are heated under reflux in 65 ml of ethanol for 12hours. 30 ml of the solvent are then evaporated and the remainingfraction is cooled to obtain a product which is purified bychromatography on a column of cilica gel-60/benzene. The elution iscarried out using a 9:1 mixture of benzene and ethyl acetate to obtain2-tetrahydrofurfuryl5-allyloxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting at 129°-131° C. The yield is 26% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.23 H.sub.26 N.sub.2 O.sub.7                                          % C        % H    % N                                               ______________________________________                                        Calculated  62.43        5.92   6.33                                          Found       62.67        5.87   6.53                                          ______________________________________                                    

IR analysis (KBr): ν(cm⁻¹): 3340, 3260, 2950, 2880, 1700, 1660, 1530,1350, 1210, 1090, 1020, 780, 750, 700.

NMR spectrum (δ, CDCl₃): p.p.m: 8.1-7.2(4H, m); 6.6(1H, s); 5.7(1H, m);5.3-4.9(4H, m); 4.5(2H, d); 4.1(2H, s); 3.8(2H, td); 2.4(6H, s); 1.9(4H,m).

EXAMPLE 23 ##STR34##

15 g (0.06 moles) of methyl 2-(3-nitrobenzylidene)acetylacetate and13.56 g (0.06 moles) of 3,3,5-trimethylcyclohexyl 3-aminocrotonate areheated under reflux in 60 ml of ethanol for 8 hours. 30 ml of solventare then evaporated, and the remaining fraction is cooled to -5° C. toobtain 3,3,5-trimethylcyclohexyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas pale yellow crystals melting--after recrystallisation in ethanol--at137°-140° C. The yield is 35% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.25 H.sub.32 N.sub.2 O.sub.6                                          % C        % H    % N                                               ______________________________________                                        Calculated  65.77        7.07   6.14                                          Found       65.71        7.35   6.07                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 2960, 2920, 1680, 1665, 1540, 1490,1360, 1230, 1130, 1020, 780, 760, 700.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.1-7.2(4H, m); 6.5(1H, m); 5.2(1H, s);5(1H, sl); 3.6(3H, s); 2.35(6H, d); 1.8-0.7(16H, m).

EXAMPLE 24 ##STR35##

21.87 g (0.06 moles) of 3,3,5-trimethylcyclohexyl2-(3-nitrobenzylidene)acetylacetate and 7.84 g (0.06 moles) of ethyl3-aminocrotonate are heated under reflux in 60 ml of ethanol for 8hours. The solution is then cooled to -5° C. to obtain3,3,5-trimethylcyclohexyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol--at125°-129° C. The yield is 37% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.26 H.sub.34 N.sub.2 O.sub.6                                          % C        % H    % N                                               ______________________________________                                        Calculated  66.36        7.28   5.95                                          Found       66.10        7.66   5.98                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3380, 2940, 1700, 1520, 1470, 1340, 1270,1200, 1090, 880, 780, 740, 710.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.3-7.3(4H, m); 6.7(1H, s); 5.3(1H, s);5.1(1H, sl); 4.2(2H, q); 2.4-0.8(25H, m).

EXAMPLE 25 ##STR36##

8.02 g (0.03 moles) of ethyl 2-(2-nitrobenzylidene)acetylacetate and9.65 g (0.03 moles) of 2-(4-acetylaminophenoxy)ethyl 3-aminocrotonateare heated under reflux in 40 ml of ethanol for 8 hours. The solution isthen cooled to -5° C. to obtain 2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylatewith half a molecule of ethanol as yellow crystals melting--afterrecrystallisation in ethanol--at 96°-108° C. The yield is 57% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.27 H.sub.29 N.sub.3 O.sub.8.1/2 C.sub.2 H.sub.6 O                    % C        % H    % N                                               ______________________________________                                        Calculated  61.53        5.90   7.69                                          Found       61.08        6.07   7.45                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3380, 3000, 1700, 1540, 1520, 1320, 1220,1120, 1025, 835, 760, 715.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.2-6.5(9H, m) 5.8(1H, s); 4.4-3.8(7H,m) 2.3(6H, s); 2.1(3H, s); 1.1(4.5H, t).

EXAMPLE 26 ##STR37##

15 g (0.05 moles) of 2-tetrahydrofurfuryl2-(2-nitrobenzylidene)acetylacetate and 13.07 g (0.05 moles) of2-(4-acetylaminophenoxy)ethyl 3-aminocrotonate are heated under refluxin 50 ml of ethanol for 8 hours. The solution is then cooled to roomtemperature to obtain 2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-4-(2-nitrophenyl)-5-(2-tetrahydrofurfuryloxycarbonyl)-1,4-dihydropyridine-3-carboxylateas yellow needles melting--after recrystallisation in ethano--at146°-150° C. The yield is 57% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.30 H.sub.33 N.sub.3 O.sub.9                                          % C        % H    % N                                               ______________________________________                                        Calculated  62.17        5.74   7.25                                          Found       61.90        5.43   6.99                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3310, 2980, 1705, 1670, 1540, 1520, 1500,1250, 1200, 1120, 1100, 1020, 830, 780, 750, 710.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 9.7(1H, s); 8.9(1H, s); 7.7-6.6(8H,m); 4.3-3.3(9H, m); 2.2(8H, s); 2.0(3H, s); 1.8-1.3(4H, m).

EXAMPLE 27 ##STR38##

13.05 g (0.05 moles) of 2-(N-salicylamido)ethyl 3-aminocrotonate and20.36 g (0.05 moles) of 2-(4-acetylaminophenoxy)ethyl2-(3-nitrobenzylidene)acetylacetate are heated under reflux in 50 ml ofabsolute alcohol for 8 hours. The solution is the cooled to -5° C. toobtain 2-(N-salicylamido)ethyl5-(2-(4-acetylaminophenoxy)ethoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow slightly hygroscopic crystals melting--after recrystallisationin absolute alcohol--at 112°-121° C. The yield is 66% of the theoreticalyield.

    ______________________________________                                        Analysis for C.sub.34 H.sub.34 N.sub.4 O.sub.10                                         % C        % H    % N                                               ______________________________________                                        Calculated  62.00        5.20   8.51                                                      62.33        4.87   8.46                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 2960, 1700, 1650, 1600, 1540, 1520,1490, 1350, 1250, 1210, 1130, 1100, 1020, 830, 780, 755, 715.

NMR spectrum (δ, CDCl₃ +DMSO-d₆): p.p.m.: 12.2(1H, s); 9.4(1H, s);8.6-6.5(14H, m); 5(1H, s); 4.4-3.8(6H, m); 3.8-3.3(2H, m); 2.3(6H, s);2.05(3H, s).

EXAMPLE 28 ##STR39##

15 g (0.05 moles) of 2-(4-acetylaminophenoxy)ethyl 3-aminocrotonate and12.63 g (0.05 moles) of methyl 2-(2-methoxybenzylidene)acetylacetate areheated under reflux in 60 ml of ethanol for 8 hours. The solution isthen cooled to -5° C. to obtain 2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(2-methoxyphenyl)-1,4-dihydropyridine-3-carboxylatewith one molecule of ethanol as a white slightly yellowish powdermelting--after recrystallisation in ethanol--at 98°-101° C. The yield is55% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.27 H.sub.30 N.sub.2 O.sub.7.C.sub.2 H.sub.6 O                        % C        % H    % N                                               ______________________________________                                        Calculated  64.43        6.71   5.18                                          Found       64.66        7.00   5.19                                          ______________________________________                                    

IR analysis (Kbr): ν(cm⁻¹): 3360, 3100, 2960, 1685, 1520, 1495, 1310,1245, 1210, 1120, 1020, 830, 760.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.4(1H, s); 7.6-6.5(10H, m); 5.3(1H,s); 4.3-3.9(4H, m); 3.8-3.4(3H+3H+2H, s+sd); 2.2-2.05(6H+3H, s+s);1.2(3H, t).

EXAMPLE 29 ##STR40##

20 g (0.05 moles) of 2-(4-acetylaminophenoxy)ethyl2-(2-nitrobenzylidene)acetylacetate and 13.5 g (0.05 moles) of2-(4-acetylaminophenoxy)ethyl 3-aminocrotonate are heated under refulxin 50 ml of ethanol for 2 hours. The solution is then cooled to roomtemperature to obtain bis-2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylatewith one molecule of ethanol as yellow crystals melting--afterrecrystallisation in ethanol--at 148°-154° C. The yield is 46% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.35 H.sub.36 N.sub.4 O.sub.10.C.sub.2 H.sub.6 O                       % C        % H    % N                                               ______________________________________                                        Calculated  61.83        5.89   7.79                                          Found       61.49        6.07   7.85                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3330, 3300, 3100, 1710, 1680, 1540, 1520,1350, 1250, 1210, 1105, 935, 840, 715.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 9.7(1H, sd); 8.9(1H, sl);7.7-6.5(14H, m); 5.65(1H, sd); 4.4-3.85(8H, sd); 3.4(2H, m);2.4-1.9(6H+6H, s+s); 1.1(3H, t).

EXAMPLE 30 ##STR41##

15 g (0.06 moles) of 2-(N-salicylamido)ethyl 3-aminocrotonate and 14.94g (0.06 moles) of ethyl 2-(3-nitrobenzylidene)acetylacetate are heatedunder reflux in 55 ml of ethanol for 8 hours. The solution is thenevaporated, 5 ml of methanol are added to the residue, and the mixtureis cooled to -5° C. to obtain 2-(N-salicylamido)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas a yellow powdre melting at 127-130. The yield is 86% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.26 H.sub.27 N.sub.3 O.sub.8                                          % C        % H    % N                                               ______________________________________                                        Calculated  61.29        5.34   8.25                                          Found       61.28        5.34   8.24                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3460, 3400, 3000, 1700, 1660, 1540, 1490,1350, 1300, 1220, 1125, 1095, 1030, 780, 750, 700.

NMR spectrum (δ, CDCl₃): p.p.m.: 12(1H, sd); 8.2-6.5(10H, m); 5.1(1H,s); 4.4-3.4(4H+2H, m) 2.3(6H, s); 1.2(3H, t).

EXAMPLE 31 ##STR42##

9 g (0.04 moles) of methyl 2-(5-nitro-2-thenylidene)acetylacetate and9.81 g (0.04 moles) of 2-(4-acetylaminophenoxy)ethyl 3-aminocrotonateare heated under reflux in 40 ml of ethanol for 1.5 hours. The solutionis then cooled to room temperature to obtain2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(5-nitro-2-thienyl)-1,4-dihydropyridine-3-carboxylateas yellow prismes melting and at the same time decomposing--afterrecrystallisation in ethanol--at 224°-226° C. The yield is 85% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.24 H.sub.25 N.sub.3 O.sub.8 S                                         % C  % H        % N    % S                                         ______________________________________                                        Calculated   55.92  4.89       8.15 6.22                                      Found        55.70  4.70       8.16 6.54                                      ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3380, 3300, 3100, 1710, 1670, 1510, 1430,1340, 1280, 1215, 1115, 1100, 1030, 840, 820, 735.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 9.7(1H, s); 9.3(1H, s); 7.9-6.7(6H,m); 5.2(1H, s); 4.5-4(2H+2H, sl+sl); 3.65(3H, s); 2.35(6H, s); 2(3H, s).

EXAMPLE 32 ##STR43##

10 g (0.04 moles) of methyl 2-(2,3-dimethoxybenzylidene)acetylacetateand 7.01 g (0.04 moles) of 2-tetrahydrofurfuryl 3-aminocrotonate areheated under reflux in 40 ml of ethanol for 8 hours. The solvent is thenevaporated and the remaining oil is dissolved in 10 ml of boiling ethylacetate. The solution is cooled to -5° C. to obtain 2-tetrahydrofurfuryl4-(2,3-dimethoxyphenyl)-2,6-dimethyl-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylateas white prisms melting--after recrystallisation in ethanol--at138°-140° C. The yield is 48% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.23 H.sub.29 NO.sub.7                                                 % C        % H    % N                                               ______________________________________                                        Calculated  64.02        6.77   3.25                                          Found       63.75        6.75   3.40                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3320, 3260, 2960, 1700, 1640, 1520, 1480,1310, 1290, 1210, 1100, 1070, 1020, 810, 740.

NMR spectrum (δ, CDCl₃): p.p.m.: 6.9(4H, sd); 5.3(1H, s);4.4-3.6(5H+6H+3H, m+s+s); 2.2(6H, s); 2.1-1.7(4H, m).

EXAMPLE 33 ##STR44##

5.02 g (0.02 moles) of ethyl 2-(3-nitrobenzylidene)acetylacetate and6.74 g (0.02 moles) of 2-(4-benzenesulfonyl-1-piperazinyl)ethyl3-aminocrotonate are heated under reflux in 20 ml of ethanol for 8hours. The solvent is then evaporated to obtain2-(4-benzenesulfonyl-1-piperazinyl)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas a yellow powder melting--after recrystallisation in ethanol--at161°-163° C. The yield is 76% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.29 H.sub.34 N.sub.4 O.sub.8 S                                         % C  % H        % N    % S                                         ______________________________________                                        Calculated   58.18  5.72       9.36 5.36                                      Found        57.89  5.63       9.42 5.72                                      ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3400, 3120, 2980, 2830, 1710, 1660, 1540,1495, 1355, 1220, 1170, 1110, 950, 740, 690.

NMR spectrum (δ, CDCl₃): p.p.m.: 8-7.1(9H, m); 6.3(1H, s); 5(1H, s);4.2-3.8(4H, m); 3.1-2.3(10H, m); 2.3(6H, s); 1.2(3H, t).

EXAMPLE 34 ##STR45##

4.94 g (0.02 moles) of methyl 2-(3-nitrobenzylidene)acetylacetate and7.0 g (0.02 moles) of 2-(4-benzenesulfonyl-1-piperazinyl)ethyl3-aminocrotonate are heated under reflux in 20 ml of ethanol for 8hours. The solution is then cooled to -5° C. to obtain2-(4-benzenesulfonyl-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow and slightly hygroscopic crystals melting while at the sametime decomposing at--after recrystallisation in absolutealcohol--106°-120° C. The yield is 65% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.28 H.sub.32 N.sub.4 O.sub.8 S                                         % C  % H        % N    % S                                         ______________________________________                                        Calculated   57.52  5.52       9.58 5.48                                      Found        57.45  5.75       9.62 5.53                                      ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 2940, 2840, 1705, 1660, 1530, 1485,1350, 1220, 1170, 1120, 1015, 950, 740, 700, 690.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.1-7.0(9H, m); 6.7(1H, s); 5(1H, s);4.1(2H, td); 3.6(3H, s); 3.2-2.2(10H+6H, m+s).

EXAMPLE 35 ##STR46##

1.11 g (2.86×10⁻³ moles) of2-(4-(4-chlorobenzenesulfonyl)-1-piperazinyl)ethyl 3-aminocrotonate and0.72 g 2.86×10⁻³ moles) of methyl 2-(3-nitrobenzylidene)acetylacetateare heated under reflux in 10 ml of ethanol for 8 hours. The solvent isthen evaporated, 3 ml of methanol are added to the residue and themixture is cooled to -5° C. to obtain2-(4-(4-chlorobenzenesulfonyl)-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas pale yellow cristals melting at 97°-105° C. while at the same timedecomposing. The yield is 69% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.28 H.sub.31 ClN.sub.4 O.sub.8 S                                    % C    % H    % H      % Cl  % S                                      ______________________________________                                        Calculated                                                                              54.32    5.05   9.05   5.73  5.18                                   Found     53.97    5.20   9.26   5.83  6.32                                   ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 3080, 2940, 2810, 1700, 1530, 1480,1350, 1210, 1170, 1090, 1010, 950, 820, 760, 700.

NMR spectrum (δ, CDCl₃): 8.1-7.2(8H, m); 6.75(1H, s) 5.1(1H, s); 4.1(2H,td); 3.6(3H, sd); 3.2-2.1(10H+6H, m+s).

EXAMPLE 36 ##STR47##

6.41 g (0.02 moles) of2-(4-(4-methoxybenzenesulfonyl)-1-piperazinyl)ethyl 3-aminocrotonate and4.17 g (0.02 mols) of methyl 2-(3-nitrobenzylidene)acetylacetate areheated under reflux in 20 ml of ethanol for 8 hours. The solvent is thenevaporated, 5 ml of boiling methanol are added to the residue to obtain2-(4-(4-methoxybenzenesulfonyl)-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylatewith one half of a molecule of ethanol as yellow crystals melting whileat the same time decomposing--after recrystallisation in ethanol--at82°-104° C. The yield is 67% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.29 H.sub.34 N.sub.4 O.sub.9 S.1/2 C.sub.2 H.sub.6 O                   % C  % N        % N    % S                                         ______________________________________                                        Calculated   56.50  5.85       8.79 5.03                                      Found        56.66  6.00       9.30 5.93                                      ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 2940, 2830, 1700, 1590, 1530, 1500,1350, 1220, 1160, 1090, 800, 730, 700.

NMR spectrum (δ, CDCl₃): p.p.m: 8.05-6.7(9H, m); 5.05(1H, s);4.2-3.3(2H+3H+3H+1H, td+s+s+m); 3.1-2.2(10CH+6H, m+s); 1.2(1/2 3H, t).

EXAMPLE 37 ##STR48##

15 g (0.05 moles) of isopropyl 2-(3-nitrobenzylidene)acetylacetate and14.30 (0.05 moles of 2-(N-salicylamido)ethyl 3-aminocrotonate are heatedunder reflux in 55 ml of ethanol for 8 hours. The solvent is thenevaporated, 15 ml of ethyl acetate are added to the residue, and themixture is cooled to 7° C. to obtain 2-(N-salicylamido)ethyl2,6-dimethyl-5-isopropoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylatewith one molecule of ethanol as yellow needles melting while at the sametime decomposing at--after recrystallisation in ethanol--107°-113° C.The yield is 70% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.27 H.sub.29 N.sub.3 O.sub.8.C.sub.2 H.sub.6 O                        % C        % H    % N                                               ______________________________________                                        Calculated  61.15        6.19   7.38                                          Found       61.45        6.07   7.62                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3340, 3080, 2960, 1680, 1660, 1640, 1530,1490, 1345, 1300, 1210, 1100, 1010, 775, 745, 695.

NMR spectrum (δ, OMSO-d₆): p.p.m.: 12.7(1H, s); 9(2H, m); 8.3-6.8(8H,m); 5.2(1H, s); 4.95(1H, m); 4.3(2H, td); 3.6(4H, m); 2.4(6H, s);1.1(9H, t). EXAMPLE 38 ##STR49##

13 g (0.05 moles) of ethyl 2-(5-nitro-2-thenylidene)acetylacetate and12.76 g (0.05 moles) of 2-(N-salicylamido)ethyl 3-aminocrotonate areheated under reflux in 100 ml of ethanol for 8 hours. The solvent isthen evaporated, and the remaining oil is dried under vacuum in thepresence of CaCl₂ to obtain 2-(N-salicylamido)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(5-nitro-2-thienyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals which are unstable and froth when exposed to lightand which melt while decomposing at the same time at 60°-75° C. Theyield is 66% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.24 H.sub.25 N.sub.3 O.sub.8 S                                         % C  % H        % N    % S                                         ______________________________________                                        Calculated   55.91  4.89       8.15 6.22                                      Found        55.87  4.89       8.19 6.45                                      ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 3100, 2980, 1700, 1650, 1600, 1500,1335, 1210, 1120, 1090, 1020, 810, 750, 730.

NMR spectrum (δ, CDCl₃): p.p.m.: 7.6-6.6(9H, m); 5.25(1H, s);4.5-3.5(6H, m); 2.3(6H, s); 1.2(3H, t).

EXAMPLE 39 ##STR50##

15 g (0.06 moles) of methyl 2-(3-nitrobenzylidene)acetylacetate and20.67 g (0.06 moles) of 2-(4-cinnamoyl-1-piperazinyl)ethyl3-aminocrotonate are heated under reflux for 8 hours in 60 ml ofethanol. The solution is then cooled to room temperature, and 1.75 ml ofethyl ether saturated with hydrogen chloride are added to obtain thechlorhydrate. The solvent is evaporated, and the residue dried undervacuum in a desiccator in the presence of CaCl₂ to obtain thechlorhydrate of 2-(4-cinnamoyl-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow frothing crystals which melt while at the same timedecomposing at 90°-150° C. The yield is 67% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.31 H.sub.34 N.sub.4 O.sub.7.HCl                                      % C  % H        % N    % Cl                                         ______________________________________                                        Calculated  60.93  5.77       9.17 5.80                                       Found       60.73  5.64       8.82 5.52                                       ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3250, 3080, 2950, 1700, 1650, 1530, 1400,1430, 1350, 1210, 1115, 1100, 1020, 760, 700.

NMR spectrum (δ, CDCl₃): p.p.m.: 8-6.6(12H, m); 5.2(1H, s); 5(1H, s);4.4(2H, m); 4-3.6 (4H+3H, m+s); 3(6H, m); 2,35(6H, sd).

EXAMPLE 40 ##STR51##

20 g (0.06 moles) of 2-tetrahydrofurfuryl2-(3-nitrobenzylidene)acetylacetate and 17.43 g (0.06 moles) of2-(4-acetylaminophenoxy)ethyl 3-aminocrotonate are heated under refluxin 60 ml of ethanol for 8 hours. The solvent is then evaporated, 25 mlof boiling ethyl acetate are added to the residue, and the mixture iscooled to 7° C. to obtain 2-(acetylaminophenoxy)ethyl2,6-dimethyl-4-(3-nitrophenyl)-5-(2-tetrahydrofurfuryloxycarbonyl)-1,4-dihydropyridine-3-carboxylatewith one molecule of ethanol as a yellow powder which afterrecrystallisation in ethyl acetate melts while at the same timedecomposes at 88°-92° C. The yield is 46% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.30 H.sub.33 N.sub.3 O.sub.9.C.sub.2 H.sub.6 O                       % C         % H    % N                                               ______________________________________                                        Calculated 61.43         6.38   6.72                                          Found      61.22         6.24   6.43                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3410, 3350, 2950, 2880, 1700, 1670, 1535,1350, 1250, 1210, 1120, 1020, 830, 750, 710.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.4-6.6(10H, m); 5.1(1H, s);4.6-3.5(11H, s); 2.35(6H, s); 2.2-1.5(7H, m); 1.25(3H, t).

EXAMPLE 41 ##STR52##

9.18 g (0.03 moles) of 3-(4-benzoyl-1-piperidinyl)propyl3-aminocrotonate and 6.92 g (0.03 moles) of methyl2-(3-nitrobenzenylidene)acetylacetate are heated under reflux in 30 mlof ethanol for 8 hours. The solvent is then evaporated, 10 ml of boilingmethanol are added to the residue, and the mixture is cooled to -5° C.to obtain 3-(4-benzoyl-1-piperidinyl)propyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol--at133°-136° C. The yield is 26% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.31 H.sub.35 N.sub.3 C.sub.7                                         % C         % H    % N                                               ______________________________________                                        Calculated 66.30         6.28   7.48                                          Found      65.97         6.56   7.18                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3380, 2960, 1705, 1680, 1660, 1530, 1485,1350, 1220, 1120, 1100, 980, 780, 745, 700.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.1-7(10H, m); 5.1(1H, s); 4.1(2H, m);3.6(3H, s); 3.5-1.5(5H+6H+8H).

EXAMPLE 42 ##STR53##

10 g (0.04 moles) of 2-(N-(4-hydroxybenzoyl)amino)ethyl 3-aminocrotonateand 9.43 g (0.04 moles) of methyl 2-(3-nitrobenzylidene)acetylacetateare heated under reflux in 40 ml of ethanol for 8 hours. The solvent isthen evaporated to obtain 2-(N-(4-hydroxybenzoyl)amino)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow frothing crystals, which melt and at the same time decomposeat 110°-120° C. The yield is 96% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.25 H.sub.25 N.sub.3 O.sub.8                                         % C         % H    % N                                               ______________________________________                                        Calculated 60.60         5.08   8.48                                          Found      60.25         5.05   8.72                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 2940, 1700, 1650, 1530, 1510, 1350,1210, 1115, 1090, 1020, 840, 760, 700.

NMR spectrum (δ, CDCl₃ +DMSO-d₆): p.p.m.: 9.4(1H, s); 8.3-6.7(10H, m);5,05(1H, s); 4.2(2H, t); 3.6(2H+3H, m+s); 2.35(6H, s).

EXAMPLE 43 ##STR54##

15 g (0.05 moles of 2-tetrahydrofurfuryl2-(3-nitrobenzylidene)acetylacetate and 12.41 g (0.05 moles) of2-(N-salicylamido)ethyl 3-aminocrotonate are heated under reflux in 50ml of ethanol for 8 hours. The solvent is then evaporated, and theremaining oil is dissolved in 30 ml of boiling aqueous ethanol (50%).The solution is then cooled to -5° C. The insoluble fraction is decantedand dried under vacuum in a dessicator and in the presence of CaCl₂ toobtain 2-(N-salicylamido)ethyl2,6-dimethyl-4-(3-nitrophenyl)-5-(2-tetrahydrofurfuryloxycarbonyl)-1,4-dihydropyridine-3-carboxylateas a yellow powder which after recrystallisation in ethanol melts whileat the same time decomposing at 115°-125° C. The yield is 66% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.29 H.sub.31 N.sub.3 O.sub.9                                         % C         % H    % N                                               ______________________________________                                        Calculated 61.59         5.52   7.43                                          Found      61.50         5.22   7.51                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3440, 3360, 2960, 2860, 1700, 1650, 1530,1490, 1340, 1220, 1120, 1015, 820, 775, 750, 690.

NMR spectrum (δ, CDCl₃): p.p.m.: 11.9(1H, sl); 8.2-6.6(10, m); 5.1(1H,s); 4.4-3.4(9H, m); 2.35(6H, s); 2.1-1.5(4H, m).

EXAMPLE 44 ##STR55##

11 g (0.04 moles) of 2-(N-(4-hydroxybenzoyl)amino)ethyl 3-aminocrotonateand 10.96 g (0.04 moles) of ethyl 2-(3-nitrobenzylidene)acetylacetateare heated under reflux in 45 ml of ethanol for 8 hours. The solution isthen dicoloured with activated charcoal and the solvent is evaporated toobtain 2-(N-(4-hydroxybenzoyl)amino)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow frothing crystals which decompose as they melt at 107°-116° C.The yield is 72% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.26 H.sub.27 N.sub.3 O.sub.8                                         % C         % H    % N                                               ______________________________________                                        Calculated 61.29         5.34   8.25                                          Found      61.98         5.51   8.25                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3350, 3080, 2980, 1690, 1645, 1610, 1530,1505, 1345, 1210, 1120, 1015, 840, 760, 740, 700.

NMR spectrum (δ, CDCl₃ +DMSO-d₆): p.p.m.: 8.4-6.6 (11H, m); 5(1H, s);4.3-3.8(4H, m); 3.5(2H, m); 2.3(6H, s); 1.15(3H, t).

EXAMPLE 45 ##STR56##

10 g (0.02 moles) of 2-(4-acetylaminobenzoyoxy)ethyl2-(3-nitrobenzylidene)acetylacetate and 3.25 g (0.02 moles) of isopropyl3-aminocrotonate are heated under reflux in 35 ml of ethanol for 8hours. The solution is then cooled to -5° C. to obtain2-(4-acetylaminobenzoyloxy)ethyl2,6-dimethyl-5-isopropoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol at193°-195° C. The yield is 65% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.29 H.sub.31 N.sub.3 O.sub.9                                         % C         % H    % N                                               ______________________________________                                        Calculated 61.59         5.52   7.43                                          Found      61.29         5.76   7.37                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3400, 3320, 3100, 2980, 1705, 1605, 1540,1500, 1410, 1360, 1260, 1210, 1095, 850, 769, 745, 710, 690.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 10.4(1H, s); 9.1(1H, s); 8.3-7.4(9H,m); 5.2-4.8(1H+1H, s+m); 4.45(4H, sl); 2.4 (6H, s); 2.2(3H, s); 1.15(6H,t).

EXAMPLE 46 ##STR57##

20 g (0.07 moles) of 2-(4-acetylaminobenzoyloxy)ethyl acetylacetate,8.41 (0.07 moles) of ethyl 3-aminocrotonate and 9.84 g (0.07 moles) of3-nitrobenzaldehyde are heated under reflux in 65 ml of ethanol for 8hours. The solvent is then evaporated, 15 ml of boiling methanol areadded to the residue, the solution is discoloured with activatedcharcoal and cooled to -5° C. to obtain 2-(4-acetylaminobenzoyloxy)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylatewith half a molecule of ethanol as yellow crystals melting--afterrecrystallisation in ehtanol--at 157°-162° C. The yield is 46% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.28 H.sub.29 N.sub.3 O.sub.9.1/2C.sub.2 H.sub.6 O                    % C         % H    % N                                               ______________________________________                                        Calculated 60.62         5.61   7.31                                          Found      60.17         5.86   7.52                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 3250, 2990, 1720, 1690, 1660, 1630,1475, 1345, 1270, 1210, 1110, 1090, 1050, 760, 746, 700.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 10.4(1H, s); 9.1(1H, s); 8.2-7.3(8H,m); 5.15(1H, s); 4.6-3.8(7H, m); 2.4(6H, s); 2.15(3H, s); 1.1(4, 5, t).

EXAMPLE 47 ##STR58##

13.27 g (0.03) moles of 2-(4-acetylaminobenzoyloxy)ethyle2-(3-nitrobenzylidene)acetylacetate, 9.26 g (0.03 moles) of2-(4-acetylaminobenzoyloxy)ethyle acetylacetate and 5 ml of a aconcentrated aqueous solution of ammonium hydroxide are heated underreflux in 50 ml of ethanol for 8 hours. 30 ml of solvent are thenevaporated and the remaining fraction is cooled to -5° C. to obtainbis-2-(4-acetylaminobenzoyloxy)ethyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate asyellow crystals melting--after recrystallisation in ethanol--at147°-150° C. The yield is 46% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.37 H.sub.36 O.sub.12                                                % C         % H    % N                                               ______________________________________                                        Calculated 60.99         4.98   7.69                                          Found      60.61         5.15   7.91                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3320, 3100, 2940, 1720, 1700, 1680, 1600,1540, 1490, 1410, 1350, 1270, 1200, 1100, 850, 760, 710.

NMR spectrum (δ, CDCl₃ +DMSO-d₆): p.p.m.: 9.9(2H, s); 8.7(1H, s);8.2-7(12H, m); 5(1H, s); 4.3(8H, s); 2.3(6H, s); 2.1(6H, s).

EXAMPLE 48 ##STR59##

15 g (0.04 moles) of 2-(N-salicylamido)ethyl2-(3-nitrobenzylidene)acetylacetate and 9.95 g (0.04 moles) of2-(N-salicylamido)ethyl 3-aminocrotonate are heated under reflux in 40ml of ethanol for 8 hours. The solvent is then evaporated and theremaining oil dissolved in 200 ml of methanol. The solution isdiscoloured with activated charcoal. The solvent is evaporated to obtainbis-2-(N-salicylamido)ethyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylatewith one molecule of ethanol as yellow frothing crystals which melt at107°-120° C. while at the same time decomposing. The yield is 74% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.33 H.sub.32 N.sub.4 O.sub.10.C.sub.2 H.sub.6 O                      % C         % H    % N                                               ______________________________________                                        Calculated 60.86         5.55   8.11                                          Found      60.46         5.42   8.33                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3400, 1700, 1640, 1600, 1530, 1350, 1490,1300, 1210, 1110, 745, 690.

NMR spectrum (δ, CDCl₃): p.p.m.: 8-6.5(18H, s); 5.05(1H, s); 4.2(4H, m);3.8-3.4(6H, m); 2.25(6H, s); 1.2(3H, t).

EXAMPLE 49 ##STR60##

15 g (0.06 moles) of 2-(N-salicylamido)ethyl 3-aminocrotonate and 13.30g (0.06 moles) of methyl 2-(2-methoxybenzylidene)acetylacetate areheated under reflux in 60 ml of ethanol for 8 hours. 30 ml of thesolvent are then evaporated, and the remaining fraction is cooled to -5°C. to obtain 2-(N-salicylamido)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(2-methoxyphenyl)-1,4-dihydropridine-3-carboxylate as pale yellow crystals melting--after recrystallisationin ethanol--at 173°-175° C. The yield is 45% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.26 H.sub.28 N.sub.2 O.sub.7                                         % C         % H    % N                                               ______________________________________                                        Calculated 64.99         5.87   5.83                                          Found      64.99         6.14   6.06                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3340, 3360, 2940, 1710, 1640, 1600, 1490,1300, 1240, 1210, 1110, 1090, 1010, 755.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 8.8(2H, m); 8.1-6.7(9H, m); 5.35(1H,s); 4.2(2H, m); 3.75(3H, s); 3.6(3H, s); 2.3(6H, s).

EXAMPLE 50 ##STR61##

15 g (0.04 moles) of 2(N-salicylamido)ethyl2-(3-nitrobenzylidene)acetylacetate and 9.39 g (0.04 moles) ofnicotinoylamino)ethyl 3-aminocrotonate are heated under reflux in 40 mlof ethanol for 8 hours. The solution is then discoloured with activatedcharcoal and the solvent is evaporated. The remaining oil isrecrystallised in H₂ O₂, extracted with CH₂ Cl₂ (2×100 ml), the ogranicphase is dried with anhydrous Na₂ SO₄ and the solvent is evaporated toobtain 2-(N-salicylamido)ethyl 2-(N-nicotinoylamino)ethyl-3-carboxylate2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate withone molecule of H₂ O₂ as yellow frothing crystals which melt while atthe same time decomposing at 88°-115° C. The yield is 51% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.32 H.sub.31 N.sub.5 O.sub.9.H.sub.2 O                               % C         % H    % N                                               ______________________________________                                        Calculated 59.35         5.10   10.82                                         Found      59.23         4.75   10.85                                         ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3320, 3060, 2940, 1640, 1600, 1530, 1490,1350, 1310, 1210, 1120, 1020, 890, 750, 700.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 12.2(1H, s); 8.9-6.7(14H, m); 5(1H,s); 4.1(4H, td); 3.5(4H, m); 3.3(2H, s); 2.25(6H, s).

EXAMPLE 51 ##STR62##

13.27 g (0.03 moles) of 2-(4-acetylaminobenzoyloxy)ethyl2-(3-nitrobenzylidene)acetylacetate and 5.58 g (0.03 moles) of2-tetrahydrofurfuryl 3-aminocrotonate are heated under reflux in 50 mlof ethanol for 8 hours. The solution is then discoloure with activatedcharcoal and the solvant evaporated to obtain2-(4-acetylaminobenzoyloxy)ethyl2,6-dimethyl-4-(3-nitrophenyl)-5-(2-tetrahydrofurfuryloxycarbonyl)-1,4-dihydropyridine-3-carboxylateas yellow frothing crystals which melt at 82°-92° C. while at the sametime decomposing. The yield is 45% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.31 H.sub.33 N.sub.3 O.sub.10                                        % C         % H    % N                                               ______________________________________                                        Calculated 61.28         5.47   6.92                                          Found      58.69         5.35   6.83                                          ______________________________________                                    

IR spectrum (KbR): ν(cm⁻¹): 3350, 2950, 2880, 1700, 1600, 1530, 1490,1350, 1270, 1210, 1090, 1010, 855, 760, 700.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.2-7(9H, m); 6.5(1H, s); 5.1(1H, s);4.4(4H, s); 4.1-3.6(3H+2H, s+m); 2.35(6H, s); 2.2(3H, s).

EXAMPLE 52 ##STR63##

15 g (0.06 moles) of 2-(N-salicylamido)ethyl 3-aminocrotonate and 14.15g (0.06 moles) of methyl 2-(2-nitrobenzylidene)acetylacetate are heatedunder reflux in 60 ml of ethanol for 8 hours. The solvent is thenevaporated, 15 ml of boiling methanol are added and the mixture iscooled to -5° C. to obtain 2-(N-salicylamido)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas yellow crystals melting--after recrystallisation in ethanol--at96°-101° C. The yield is 77% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.25 H.sub.25 N.sub.3 O.sub.8                                         % C         % H    % N                                               ______________________________________                                        Calculated 60.60         5.09   8.48                                          Found      60.20         4.94   8.45                                          ______________________________________                                    

IR analysis (KBr): ν(cm⁻¹): 3380, 3080, 2960, 1710, 1650, 1600, 1540,1500, 1360, 1310, 1215, 1090, 1020, 830, 750, 710.

NMR analysis (δ, CDCl₃): p.p.m.: 12.2(1H, s); 7.6-6.5(10H, m); 5.7(1H,s); 4.2(2H, sl); 3.55(2H+3H, m+s); 2.3(6H, d).

EXAMPLE 53 ##STR64##

20 g (0.05 moles) of 2-(4-acetylaminobenzoyloxy)ethyl2-(3-nitrobenzylidene)acetylacetate and 5.23 g (0.05 moles) of methyl3-aminocrotonate are heated under reflux in 45 ml of ethanol for 8hours. The solution is then cooled to room temperature to obtain2-(4-acetylaminobenzoyloxy)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas a yellow powder melting at 190°-193° C. The yield is 94% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.27 H.sub.27 N.sub.3 O.sub.9                                         % C         % H    % N                                               ______________________________________                                        Calculated 60.33         5.06   7.82                                          Found      60.14         5.02   7.89                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 3240, 3100, 2960, 1720, 1700, 1660,1530, 1480, 1350, 1270, 1210, 1110, 1090, 1000, 760, 700, 670.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 10.1(1H, s); 8.9(1H, s); 8-7.2(8H,m); 5(1H, s); 4.4(4H, sl); 3.5(3H, s); 2.35(6H, s); 2.1(3H, s).

EXAMPLE 54 ##STR65##

15 g (0.04 moles) of 2-(N-salicylamido)ethyl2-(3-nitrobenzylidene)acetylacetate and 9.95 g (0.04 moles) of2-(N-(4-hydroxybenzoyl)amino)ethyl 3-aminocrotonate are heated underreflux in ethanol for 8 hours. The solution is then discoloured withactivated charcoal, and the solvent evaporated to obtain2-(N-salicylamido)ethyl 2-(N-(4-hydroxybenzoyl)amino)ethyl-3-carboxylate2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate withone molecule of ethanol as yellow frothing crystals which melt anddecompose at the same time at 75°-100° C. The yield is 78% of thetheoretical yield.

    ______________________________________                                        Analysis for C.sub.33 H.sub.32 N.sub.4 O.sub.10.C.sub.2 H.sub.6 O                      % C         % H    % N                                               ______________________________________                                        Calculated 60.86         5.55   8.11                                          Found      60.55         5.26   7.95                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3360, 2960, 1700, 1650, 1495, 1350, 1210,1120, 1040, 840, 750, 700.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 8.2-6.6(17H, m); 5(1H, s); 4.15(4H,sl); 3.7-3.3(6H, m); 2.3(6H, s); 1.1(3H, t).

EXAMPLE 55 ##STR66##

10 g (0.03 moles) of 2-(4-acetylaminobenzoyloxy)ethyl2-(3-nitrobenzylidene)acetylacetate and 9 g (0.03 moles) of2-(N-salicylamido)ethyl 3-aminocrotonate are heated under reflux in 40ml of ethanol for 12 hours. 20 ml of the solvent are then evaporated andthe remaining fraction is cooled to -5° C. to obtain2-(4-acetylaminobenzoyloxy)ethyl 2-(N-salicylamido)ethyl-3-carboxylate2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate asyellow crystals melting--after recrystallisation in aqueous 70%ethanol--at 184°-186° C. The yield is 85% of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.35 H.sub.34 N.sub.4 O.sub.11                                        % C         % H    % N                                               ______________________________________                                        Calculated 61.22         4.99   8.16                                          Found      61.11         5.08   8.01                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3400, 2960, 1710, 1690, 1600, 1530, 1490,1350, 1270, 1200, 1120, 1090, 860, 770, 740, 700.

NMR spectrum (δ, DMSO-d₆): p.p.m.: 12.3(1H, sl); 10.1(1H, s); 9-8.7(2H,m); 8.1-6.8(12H, m); 5.05(1H, s); 4.35(6H, m); 3.55(2H, sl); 2.35(6H,s); 2.15(3H, s).

EXAMPLE 56 ##STR67##

15 g (0.04 moles) of 2-(N-salicylamido)ethyl2-(3-nitrobenzylidene)acetylacetate and 5.99 g (0.04 moles) of2-methoxyethyl 3-aminocrotonate are heated under reflux in 40 ml ofethanol for 10 hours. The solution is then discoloured with activatedcharcoal, the solvent evaporated and the remaining oil dried undervacuum in a desiccator in the presence of CaCl₂ to obtain2-(N-salicylamido)ethyl2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylateas frothing yellow crystals, which melt at 69°-80° C. The yield is 70%of the theoretical yield.

    ______________________________________                                        Analysis for C.sub.27 H.sub.29 N.sub.3 O.sub.9                                         % C         % H    % N                                               ______________________________________                                        Calculated 60.11         5.42   7.79                                          Found      60.30         5.22   7.58                                          ______________________________________                                    

IR spectrum (KBr): ν(cm⁻¹): 3370, 3100, 2950, 1700, 1650, 1530, 1490,1350, 1210, 1115, 1090, 1020, 780, 750, 700.

NMR spectrum (δ, CDCl₃): p.p.m.: 8.1-6.5(11H, m); 5.1(1H, s); 4.2(4H,td); 3.6(4H, td); 3.3(3H, s); 2.35(6H, s).

What is claimed is:
 1. A compound selected from the group consisting ofesters of 1,4-dihydropyridine having the following formula ##STR68## inwhich: R is hydrogen or, a saturated or an unsaturated hydrocarbonradical; R₂ and R₃, which can be identical or different, are hydrogen ora straight chain alkyl group; R₄ is hydrogen or a straight alkyl chain;nis a number equaling 0, 1, 2 or 3; X is a phenyl radical which can haveone to three substituents independently selected from the groupconsisting of nitro, cyano, azido, alkoxy, alkyl, hydroxy, alkanoyloxy,carbalkoxy, amino, alkanoyl, alkylamino, S(O)_(m) -alkyl where m equals0, 1 or 2, phenyl, trifluoromethyl or halo; R₁ is a straight orbranched, saturated, unsaturated or cyclic hydrocarbon radical which canbe interrupted by one or two atoms of oxygen or sulfur and which can besubstituted by one or two hydroxyl groups; R₁ can also designate the##STR69## group; where Y is a N-substituted amide of nicotinic,salicylic or hydroxybenzoic acid or a monoalkylated, monoacylated orsulfonated N-substituted piperazine of the formula ##STR70## where R₅ isan acetyl, 2-furoyl, 2-thiophenecarbonyl, cinnamoyl or an arylsulfonylradical; or Y is a N-(4-benzoyl-piperidinyl) group; and salts thereof.2. A compound according to claim 1 in which:R is hydrogen, R₂ and R₃ aremethyl, R₄ is hydrogen, X is a phenyl group with one or two substituentsindependently selected from the group consisting of nitro and methoxy, nis a number equaling 0, 1 or 2, R₁ is a C₁ to C₄ alkyl group, analkoxyalkyl group with 1 or 2 carbon atoms in the alkyl portion and 1 to3 carbon atoms in the alkoxy portion, an alkylthioalkyl group with 1 to3 carbon atoms in the alkyl portion and in the thioalkyl portion,3,3,5-trimethylcyclohexyl or allyl, and Y is an N-substituted amide ofnicotinic, salicylic or hydroxybenzoic acid.
 3. A compound according toclaim 1 selected from the group consisting of 2-(N-nicotinoylamino)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine;2-(N-nicotinoylamino)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-nicotinoylamino)ethyl2,6-dimethyl-5-(2-methylthioethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-salicylamido)ethyl2,6-dimethyl-5-methoxycarbonyl-5-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(4-(2-furoyl)-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(4-(2-furoyl)-1-piperazinyl)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-salicylamido)ethyl2,6-dimethyl-5-methoxycarbonyl-5-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(4-(2-furoyl)-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(4-(2-furoyl)-1-piperazinyl)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(4-cinnamoyl-1-piperazinyl)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-salicylamido)ethyl5-(2-(4-acetylaminophenoxy)ethoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-salicylamido)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-4-carboxylate;2-(4-benzenesulfonyl-1-piperazinyl)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(4-benzenesulfonyl-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(4-(4-chlorobenzenesulfonyl)-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(4-(4-chlorobenzenesulfonyl)-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(4-(4-methoxybenzenesulfonyl)-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-salicylamido)ethyl2,6-dimethyl-5-isopropoxycarbonyl-5-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-salicylamido)ethyl2,6-dimethyl-5-ethoxycarbonyl-5-(5-nitro-2-thienyl)-1,4-dihydropyridine-3-carboxylate;2-(4-cinnamoyl-1-piperazinyl)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(4-acetylaminophenoxy)ethyl2,6-dimethyl-4-(3-nitrophenyl-5-(2-tetrahydrofurfuryoxycarbonyl)-1,4-dihydropyridine-3-carboxylate;3-(4-benzoyl-1-piperidinyl)propyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-(4-hydroxybenzoyl)amino)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-salicylamido)ethyl2,6-dimethyl-4-(3-nitrophenyl)-5-(2-tetrahydrofurfuryloxycarbonyl)-1,4-dihydropyridine-3-carboxylate;2-(N-(4-hydroxybenzoyl)amino)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate.2-(N-(4-hydroxybenzoyl)amino)ethyl2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;bis-2-(N-salicylamido)ethyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;2-(N-salicylamido)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(2-methoxyphenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-salicylamido)ethyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-salicylamido)ethyl2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylate;2-(N-salicylamido)ethyl2-(N-(4-hydroxybenzoyl)amino)ethyl-3-carboxylate-2,6-dimethyl-4-(3-nitrophenyl-1,4-dihydropyridine-5-carboxylate;2-(4-acetylaminobenzoyloxy)ethyl 2-(N-salicylamido)ethyl-3-carboxylate2,6-dimethyl-4-(3-nitropohenyl)-1,4-dihydropyridine-5-carboxylate; and2-(N-salicylamido)ethyl2,6-dimethyl-5-(2-methoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate.4. A pharmaceutical composition for the treatment of atheroma, whichcomprises at least one ester of dihydropyridine according to claim 1, inan amount effective to exert an anti-atheromatic effect, together with apharmaceutically acceptable diluent or carrier.
 5. A pharmaceuticalcomposition according to claim 4, containing 5-500 mg of at least one ofsaid esters of dihydropyridine.